By Grant J. Anhalt, M.D. and Hossein Nousari, M.D.
Johns Hopkins University, School of Medicine
In February 1997, the FDA approved a new drug, mycophenolate mofetil (MFM, also known as Cellcept) with an approved indication for use in immunosuppression of patients that have received renal transplants, to prevent graft rejection. MFM is actually a new variant of a drug that has been studied for about 20 years. The active metabolite, Mycophenolic acid (MPA) had been used in the past for the treatment of severe recalcitrant psoriasis.
Although MPA was shown to be a useful drug, it was withdrawn due to a high incidence of side effects, primarily infections such as herpes zoster ("shingles") and gastrointestinal side effects such as nausea and stomach discomfort. MFM is the reformulated product that does not have these same drawbacks, and has better bioavailability than MFA.
This drug is commonly used in combination with cyclosporin and corticosteroids to prevent renal graft rejection. However, the role of MFM in immunologic-mediated skin diseases such as pemphigus and bullous pemphigoid seems to be promising. For example, its therapeutic profile and toxicities make it an attractive substitute for azathioprine (Imuran) in several circumstances.
For example, it could be useful in those patients who can not tolerate azathioprine due to nausea or hepatotoxic reactions, or in those patients who are at risk for azathioprine-induced toxicities due to deficiency of the enzyme thiopurine methyl transferase. The drug may have some advantages over azathioprine, in that it may be less mutagenic than azathioprine. That means that it may confer a lower risk of malignancies such as leukemia or lymphoma arising as a result of its use. This advantage is not proven, however, and it may be a very long time before this possible advantage can be substantiated. It is also not clear as yet whether it is actually as effective in practice as is azathioprine.
There are some early encouraging reports of its usefulness, referenced at the end of this article. Reports from Germany show that it is effective, when used in combination with Prednisone, in pemphigus vulgaris. Our own experience has shown that some patients who can not tolerate azathioprine (usually due to nausea or abnormal liver enzymes) will tolerate MFM. Several patients have shown a good response to the drug, but in a couple of others it is not yet clear how effective it will be in suppressing activity of the pemphigus. We have not observed any serious side effects from the drug as yet. MFM is always used in combination with Prednisone. There is some early experience that it can be used without Prednisone to control some cases of bullous pemphigoid, but pemphigoid is quite different from pemphigus. There is no reasonable expectation that MFM could be used as monotherapy (without concurrent use of Prednisone) in pemphigus vulgaris. It is however, important to recognize that MFM is an additional agent that now can be considered for use in control of pemphigus vulgaris. For those who are interested in more details, some technical data and references follow.
MFM is an ethylester of mycophenolic acid which is metabolized to the active drug mycophenolic acid (MPA). MPA is a product of several Penicillium species. This immunomodulatory drug selectively inhibits inosine monophosphate dehydrogenase (IMPDH) in the denovo pathway of purine synthesis. This enzyme converts inosine monophosphate to xanthine monophosphate, an intermediate metabolite in the synthesis of guanosine triphosphate. This drug is more active in its inhibition of the type II isoform of IMPDH, which is found mostly in lymphocytes, and thus inhibits purine synthesis with potent cytostatic effects on both T and B lymphocytes. Lymphocytes are quite susceptible to this drug effect, for they minimally utilize the hypoxanthine-guanine phosphoribosyl transferase salvage pathway for purine synthesis. Through these actions, MFM inhibits lymphocyte proliferation and antibody formation. This drug also inhibits leukocyte recruitment and glycosylation of lymphocyte glycoproteins involved in adhesion to endothelial cells. The drug is rapidly absorbed after oral administration, and antacids and cholestyramine may decrease its absorption. Around 5% of the drug is bound to albumin. It is nearly completely metabolized by glucuronyl transferase and over 90% of the drug is eliminated by the kidneys . The MFM glucuronide metabolite, which is increased in renal failure, increases MFM clearance by competing for its binding sites on albumin. MFM pharmacokinetics seems not to be affected by the concomitant administration of CsA.
The usual dose is one gm. every 12 hours. Potential side effects include nausea, stomach upset, vomiting, and diarrhea. There is no increase in nephrotoxicity, hepatotoxicity, hypertension, or neurotoxicity when MFM is used in conjunction with CsA and costicosteroids. Severe leukopenia (decrease in white cell count) has been reported in less than 3% of MFM-treated patients.
An increased incidence of lymphoproliferative diseases and lymphoma is reported with its use, as is some predisposition for infectious complications, but it is not established whether these are lower than those observed with the use of azathioprine.
References:
Gomez E.C., Menendez L., Frost P. Efficacy of mycophenolic acid for the treatment of psoriasis. J Am Acad Derm.:531-537, 1979. Enk AH and Knop J. Treatment of pemphigus vulgaris with mycophenolate mofetil. Lancet: 350, No. 9076. Page 494, 1997. Beissert S., et al. Mycophenolate mofetil (MMF) in the treatment of bullous autoimmune skin disorders. Poster presentation # P-168A, American Academy of Dermatology Meeting, Orlando, Fla. March 1998. Silverman J.E., et al. Rediscovering mycophenolic acid: A review of its mechanisms, side effects, and potential uses. Journal of the American Academy of Dermatology. 37: 445- 449, 1997. Bohm M., Beissert S, Schwarz T et al. Bullous pemphigoid treated with mycophenolate mofetil. Lancet 349: 541, 1997. Disclosure: Dr. Anhalt and Dr. Nousari have no financial interest in the manufacturer of Cellcept or Roche Pharmaceuticals, and have received no compensation for its development or promotion.
